The aim of the proposed study is to evaluate the effects of high dose nicotine (HDN) infusion on nicotine self-administration (NSA) in rats. HDN safety and pharmacokinetics will also be studied. The long term goal of this work is to evaluate the potential of HDN as an adjunct to smoking cessation in patients refractory to standard therapies. Nicotine replacement therapy enhances smoking cessation rates, but most quit attempts are still unsuccessful. However, nicotine replacement therapy typically provides venous plasma nicotine concentrations that are substantially lower than those associated with smoking. Higher than usual doses of nicotine replacement, e.g. 2 nicotine patches at once, have been only equivocally successful in enhancing quit rates compared to usual doses, but even these higher doses do not provide the very high arterial nicotine concentrations associated with cigarette smoking. Whether even higher doses of nicotine (providing smokers with venous and arterial nicotine concentrations exceeding those experienced during normal smoking) would confer additional benefit is not known. Potential advantages of this level of HDN include more complete suppression of withdrawal, craving, and the rewarding effects of smoking. Hvpotheses to be tested are that 1) HDN suppresses the maintenance and reinstatement of NSA, 2) RDN is safe owing to the rapid development of tolerance to its adverse effects, 3) HDN efficacy can be augmented by combining it with the nicotinic antagonist mecamylamine, 4) the pharmacokinetics of HDN is similar to that of usual replacement doses, and 5) HDN reduces the formation of some carcinogens from tobacco. Studies will be performed in rats because the safety of administering HDN at the proposed doses to humans is untested. The effects of HDN on the maintenance of ongoing NSA and the reinstatement of nicotine responding will be examined. A range of both HDN doses and NSA doses will be used to establish dose-response relationships. The physiologic effects and safety of these treatments will be evaluated. HDN will be combined with the nicotinic antagonist mecamylamine to determine whether this combination is more effective than HDN alone, or better tolerated. The pharmacokinetics of HDN compared to usual nicotine replacement doses will be studied to aid in HDN dose selection. The formation of carcinogenic metabolites from the tobacco nitrosarnine NNK will be studied to determine whether this rate is altered when HDN and NNK are co-administered. Taken together, these studies will address the feasibility of using HDN as an adjunct to the initiation or maintenance of smoking cessation, and whether it is safe enough for testing in humans.